Advertisement

Cancer Immunology, Immunotherapy

, Volume 63, Issue 2, pp 111–119 | Cite as

Critical role of spatial interaction between CD8+ and Foxp3+ cells in human gastric cancer: the distance matters

  • Anita Feichtenbeiner
  • Matthias Haas
  • Maike Büttner
  • Gerhard G. Grabenbauer
  • Rainer Fietkau
  • Luitpold V. DistelEmail author
Original Article

Abstract

Purpose

In various cancer types, an abundance of FoxP3+ regulatory T cells (Treg) has been associated with an unfavorable outcome. Yet, the role of Treg on cancer immunity has been shown to be complex. In single cell marker technique, other tumor-infiltrating lymphocytes (TILs) such as cytotoxic CD8+ T cells (CTL) also influenced prognosis. This study for the first time investigates the concurrent spatial distribution pattern of CD8+ and FoxP3+ TILs and their prognostic impact in human gastric cancer.

Materials and methods

Tumor tissue microarrays of 50 patients with surgically treated adenocarcinoma of the cardia were studied. An immunohistochemical double staining of CD8+ and FoxP3+ TILs was performed. Cell counts and cell-to-cell distances in tumor epithelium and stroma were evaluated with image-processing software. Metastasis-free survival, no-evidence-of-disease survival, and overall survival were investigated (mean follow-up time 6.9 years).

Results

High intraepithelial infiltration of CD8+ and FoxP3+ TIL was associated with the improved 10-year metastasis-free survival (83 vs. 54 %, p = 0.04 and 85 vs. 59 %, p = 0.09, respectively). Considering cell-to-cell distance and comparing patients with functional (30–110 μm) versus nonfunctional distances of CD8+ and FoxP3+ TILs, 10-year survival rates differed between 89 and 55 % (p = 0.009), respectively.

Conclusion

Prognostic influence of tumor-infiltrating immune cells in gastric cancer critically depends on their cell-to-cell distance. FoxP3+ TILs must be located within a distance between 30 and 110 μm of CD8+ T cells to positively impact on prognosis.

Keywords

Regulatory T cells Cytotoxic T cells Tumor-infiltrating lymphocytes Gastric cancer Cancer immunology Immune evasion 

Notes

Acknowledgments

We thank Christa Winkelmann for excellent technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

262_2013_1491_MOESM1_ESM.pdf (3.9 mb)
Supplementary material 1 (PDF 4023 kb)

References

  1. 1.
    Piccirillo CA, Thornton AM (2004) Cornerstone of peripheral tolerance: naturally occurring CD4+ CD25+ regulatory T cells. Trends Immunol 25:374–380. doi: 10.1016/j.it.2004.04.009 PubMedCrossRefGoogle Scholar
  2. 2.
    Mathai AM, Kapadia MJ, Alexander J, Kernochan LE, Swanson PE, Yeh MM (2012) Role of Foxp3-positive tumor-infiltrating lymphocytes in the histologic features and clinical outcomes of hepatocellular carcinoma. Am J Surg Pathol 36:980–986. doi: 10.1097/PAS.0b013e31824e9b7c PubMedCrossRefGoogle Scholar
  3. 3.
    Perrone G, Ruffini PA, Catalano V et al (2008) Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer 44:1875–1882. doi: 10.1016/j.ejca.2008.05.017 PubMedCrossRefGoogle Scholar
  4. 4.
    Yuan XL, Chen L, Li MX et al (2010) Elevated expression of Foxp3 in tumor-infiltrating Treg cells suppresses T-cell proliferation and contributes to gastric cancer progression in a COX-2-dependent manner. Clin Immunol 134:277–288. doi: 10.1016/j.clim.2009.10.005 PubMedCrossRefGoogle Scholar
  5. 5.
    Distel L, Buttner M (2012) Radiochemotherapy fosters a favorable pattern of inflammatory cells in head and neck tumors. Oncoimmunology 1:982–983. doi: 10.4161/onci.20200 PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Wang B, Xu D, Yu X, Ding T, Rao H, Zhan Y, Zheng L, Li L (2011) Association of intra-tumoral infiltrating macrophages and regulatory T cells is an independent prognostic factor in gastric cancer after radical resection. Ann Surg Oncol 18:2585–2593. doi: 10.1245/s10434-011-1609-3 PubMedCrossRefGoogle Scholar
  7. 7.
    Mizukami Y, Kono K, Kawaguchi Y, Akaike H, Kamimura K, Sugai H, Fujii H (2008) Localisation pattern of Foxp3 + regulatory T cells is associated with clinical behaviour in gastric cancer. Br J Cancer 98:148–153. doi: 10.1038/sj.bjc.6604149 PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Powell J, McConkey CC (1990) Increasing incidence of adenocarcinoma of the gastric cardia and adjacent sites. Br J Cancer 62:440–443PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Giordano A, Cito L (2012) Advances in gastric cancer prevention. World J Clin Oncol 3:128–136. doi: 10.5306/wjco.v3.i9.128 PubMedCentralPubMedGoogle Scholar
  10. 10.
    Ohno S, Tachibana M, Fujii T, Ueda S, Kubota H, Nagasue N (2002) Role of stromal collagen in immunomodulation and prognosis of advanced gastric carcinoma. Int J Cancer 97:770–774PubMedCrossRefGoogle Scholar
  11. 11.
    Jung AC, Guihard S, Krugell S et al (2012) CD8-alpha T-cell infiltration in human papillomavirus-related oropharyngeal carcinoma correlates with improved patient prognosis. Int J Cancer. doi: 10.1002/ijc.27776 Google Scholar
  12. 12.
    Okuyama T, Higashi T, Edagawa A et al (2012) Ten-year survival of curability B gastric cancer patients treated by tegafur-uracil as postoperative adjuvant chemotherapy in a common public hospital: univariate and multivariate analyses. Fukuoka Acta Med 103:138–144PubMedGoogle Scholar
  13. 13.
    Haas M, Buttner M, Rau TT, Fietkau R, Grabenbauer GG, Distel LV (2011) Inflammation in gastric adenocarcinoma of the cardia: how do EBV infection, Her2 amplification and cancer progression influence tumor-infiltrating lymphocytes? Virchows Arch 458:403–411. doi: 10.1007/s00428-011-1058-1 PubMedCrossRefGoogle Scholar
  14. 14.
    Haas M, Dimmler A, Hohenberger W, Grabenbauer GG, Niedobitek G, Distel LV (2009) Stromal regulatory T-cells are associated with a favourable prognosis in gastric cancer of the cardia. BMC Gastroenterol 9:65. doi: 10.1186/1471-230X-9-65 PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Ishigami S, Arigami T, Uenosono Y et al (2012) Cancerous HLA class I expression and regulatory T cell infiltration in gastric cancer. Cancer Immunol Immunother 61:1663–1669. doi: 10.1007/s00262-012-1225-5 PubMedCrossRefGoogle Scholar
  16. 16.
    Kono K, Kawaida H, Takahashi A, Sugai H, Mimura K, Miyagawa N, Omata H, Fujii H (2006) CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother 55:1064–1071PubMedCrossRefGoogle Scholar
  17. 17.
    Lee HE, Park DJ, Kim WH, Kim HH, Lee HS (2011) High FOXP3 + regulatory T-cell density in the sentinel lymph node is associated with downstream non-sentinel lymph-node metastasis in gastric cancer. Br J Cancer 105:413–419. doi: 10.1038/bjc.2011.248 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Peng LS, Zhuang Y, Shi Y et al (2012) Increased tumor-infiltrating CD8(+)Foxp3(+) T lymphocytes are associated with tumor progression in human gastric cancer. Cancer Immunol Immunother 61:2183–2192. doi: 10.1007/s00262-012-1277-6 PubMedCrossRefGoogle Scholar
  19. 19.
    Shen Z, Zhou S, Wang Y, Li RL, Zhong C, Liang C, Sun Y (2010) Higher intratumoral infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer. J Cancer Res Clin Oncol 136:1585–1595. doi: 10.1007/s00432-010-0816-9 PubMedCrossRefGoogle Scholar
  20. 20.
    Chew A, Salama P, Robbshaw A, Klopcic B, Zeps N, Platell C, Lawrance IC (2011) SPARC, FOXP3, CD8 and CD45 correlation with disease recurrence and long-term disease-free survival in colorectal cancer. PLoS ONE 6:e22047. doi: 10.1371/journal.pone.0022047 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192. doi: 10.1200/JCO.2008.18.7229 PubMedCrossRefGoogle Scholar
  22. 22.
    Whiteside TL, Schuler P, Schilling B (2012) Induced and natural regulatory T cells in human cancer. Expert Opin Biol Ther 12:1383–1397. doi: 10.1517/14712598.2012.707184 PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Wang LH, Su L, Wang JT (2010) Correlation between elevated FOXP3 expression and increased lymph node metastasis of gastric cancer. Chin Med J 123:3545–3549PubMedGoogle Scholar
  24. 24.
    Heckman KL, Schenk EL, Radhakrishnan S, Pavelko KD, Hansen MJ, Pease LR (2007) Fast-tracked CTL: rapid induction of potent anti-tumor killer T cells in situ. Eur J Immunol 37:1827–1835. doi: 10.1002/eji.200637002 PubMedCrossRefGoogle Scholar
  25. 25.
    Kawaida H, Kono K, Takahashi A, Sugai H, Mimura K, Miyagawa N, Omata H, Ooi A, Fujii H (2005) Distribution of CD4+ CD25high regulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer. J Surg Res 124:151–157PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Anita Feichtenbeiner
    • 1
  • Matthias Haas
    • 3
  • Maike Büttner
    • 2
  • Gerhard G. Grabenbauer
    • 1
  • Rainer Fietkau
    • 1
  • Luitpold V. Distel
    • 1
    Email author
  1. 1.Department of Radiation Oncology of the University HospitalsFriedrich-Alexander-University of Erlangen-NürnbergErlangenGermany
  2. 2.Institute of Pathology of the University HospitalsFriedrich-Alexander-University of Erlangen-NürnbergErlangenGermany
  3. 3.Department of RadiologyCharité UniversitätsmedizinBerlinGermany

Personalised recommendations